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Genetic counseling: Prader-Willi Syndrome - Prenatal
Prader-Willi Syndrome - Prenatal Introduction *Discuss the reason for referral. *Elicit prior knowledge about Prader-Willi syndrome. *Elicit prior knowledge about prenatal diagnosis. *Assess concerns and set goals for the session. *Provide overview of topics for counseling session. Client & Partner Information *Discuss why it's important to get pregnancy, personal, and family history. **Explain that it is a way to identify other potential risk factors **Use examples: seizure medication, diabetes, etc. *Go over pregnancy history: **How has the pregnancy been going? **G1P1? Any stillbirths? Spontaneous or elective abortions? **Was the pregnancy planned? If so, how long did it take to become pregnant? **LMP? EDC? **Any bleeding? **Any illnesses during the pregnancy? ***Infection, cold, rash, fever? **Any chronic illnesses? **Any exposures during the pregnancy? ***X-rays, smoking, alcohol, recreational drugs? **Medications: ***Currently? ***Earlier in the pregnancy? *Personal background: **Occupation? **Do you have a religious preference? **Psychosocial assessment ***Financial, insurance concerns? ***Support system? **Information about the father: ***Name, age, occupation? ***Any exposures? ***Any chronic illnesses? Elicit History *Construct pedigree: **Abnormal # miscarriages, stillbirths, infant deaths? **Previous children with chromosome abnormality, Down syndrome, birth defects, mental retardation? **Consanguinity? Ethnicity? Other concerns/risk factors? What is Prader-Willi Syndrome? *A complex, multi-system mental retardation disorder *The first recognized microdeletion syndrome identified when high-resolution chromosome analysis was introduced *Now known to be one of the most common microdeletion syndromes *Also one of the most common recognized genetic forms of obesity *Caused by several different genetic alterations of proximal chromosome 15q Etiology & Incidence *History **Prader-Willi syndrome was first described in 1956. *The basis of Prader-Willi syndrome **Caused by the lack of expression of normally active paternally inherited genes at chromosome 15q11-q13 **The maternally inherited genes are normally inactive due to genetic imprinting ***Imprinting is a phenomenon by which some genes are modified in different ways depending on the genederof the parent from whom they were inherited **There are 3 ways in which P-W syndrome can be caused. ***Small deletion in the paternally contributed chromosome 15 ****This is seen in 75% of patients ****Usually the deletion is 4-Mb or smaller ***Uniparental disomy 15 (UPD) ****Inheritance of 2 maternal chromomes 15 but no paternal chromosome 15 ***Defect in the imprinting process ****Seen in approximately 1% of patients ****Very small deletion or other abnormality in the imprinting center ****All studied families in which there has been a recurrence of P-W have had an imprinting mutation. **The actual genes whose deficiency that cause the phenotype have not yet been identified **One-third of patients with P-W exhibit hypopigmentation due to deletion of a gene associated with tyrosinase-positive albinism *Incidence **1 in 10,000 - 15,000 **Occurs in both sexes and all races **Diagnosis is often delayed or missed in many cases Clinical Features & Natural History *Neonatal hypotonia and failure to thrive **Hypotonia is prenatal in onset and nearly uniformly present **Causes decreased fetal movement, frequent abnormal fetal position, and difficulty at time of delivery **State of hypoarousal are associated with poor suck and lack of awakening to feed **Hypotonia gradually improves **Motor milestones are delayed ***Average age of sitting is 12 months ***Average age of walking is 24 months **It is recommended that all newborns with persistent hypotonia be tested for P-W *Developmental delay and mild cognitive impairment **Language development is delayed ***Speech is often poorly articulated, having a nasal and/or slurred character **Most patients are mildly retarded ***Mean IQ 60s to low 70s **Approximately 40% have borderline retardation or low normal intelligence **20% have moderate retardation *Characteristic facial appearance **Narrow bifrontal diameter **Almond-shaped palpebral fissures **Narrow nasal bridge **Downturned mouth with a thin upper lip *Early-childhood-onset obesity **Hyperphagia begins generally between ages 2 and 4 leading to significant obesity **Hypothalamic abnormality results in lack of satiety **There is a decreased caloric requirement likely related to hypotonia and decreased activity **Food seeking behaior with hoarding or faraging for food and stealing food or money to buy food are common **High threshold for vomiting may complicate binging on spoiled food **The obesity is central in distribution, with relative sparing of the distal extremities **Obesity is the major cause of morbidity and mortality in P-W syndrome *Hypogonadism with genital hypoplasia **Hypogonadism is prenatal in onset and persists throughout life **Genital hypoplasia is evident at birth **Pubertal development is abnormal **In both males and females, sexual activity is uncommon and fertility is rare *Mild short stature **If not apparent in childhood, it is almost always present by the second half of the second decade **Average height is 155cm for males and 148cm for females **African-Americans tend to be taller *Characteristic behavior profile **Becomes evident in early childhood **Tempor tantrums, stubbornness, controlling and manipulative behavior **Obsessive-compulsive characteristics **Difficulty with change in routing **Lying, stealing, and aggressive behavior **True psychosis is evident in young adulthood in approximately 5-10% *Sleep disturbances **Excessive daytime sleepiness and oxygen desaturation in REM sleep **These are common even in the absence of obesity Inheritance *P-W is caused by a lack of expression of the paternally derived PWS/AS region of chromosome 15q11-q13 by one of several genetic mechanisms *Deletion of PWS/AS region **70% of patients have P-W syndrome by this genetic mechanism **<1% risk to siblings of an affected proband **Most of these cases are de novo deletions **A small number of cases are due to translocation with a concomitant deltion **If a parent has a balanced chromosomal translocation the recurrence risk could be as high as 25% *Uniparental disomy **25% of patients have P-W syndrome by this genetic mechanism **<1% risk to siblings of an affected proband *Imprinting defect **<5% of patients have P-W syndrome by this genetic mechanism **The risk to siblings of an affected proband is up to 50% **A healthy parent can carry this imprinting defect **But recurrence risk may be lower because imprinting defects can be de novo mutations *Balanced chromosome translocation within 15q11-q13 or abnormality **<1% of patients have P-W syndrome by this genetic mechanism **All of these cases have been de novo **Risk to siblings of an affected proband is <1% **If a familial case is detected, the theoretical risk of inheritance of the balanced translocation could be as high as 25% Diagnosis *Genetic testing **Molecular Genetic Testing ***Testing for the parent-specific methylation imprint detects over 99% of cases and is highly specific ***Methylation-specific testing is important to confirm the diagnosis in all children ***The methylation abnormality can be determined by southern blot hybridization using a methylation-sensitive probe (SNRPN or PW71B) or with parent-specific PCR primers ***If the methylation pattern is characteristic of maternal inheritance only, then the diagnosis is confirmed ***DNA methylation testing detects all cases caused by deletions, UPD, and imprinting defects ***Once the diagnosis is established, further tests are done to classify the mutation ****Deletions can be detected using FISH analysis ****UPD can be detected with informative microsatellite markers ****An imprinting defect is presumed to be present in patients with an abnormality in the parent-specific methylation imprint without evidence of a deletion or UPD **Cytogenetic Analysis ***1% of patients have a detected chromosomal rearrangement resulting in a deletion of bands 15q11-q13 ***Deletion can be detected using high resolution chromosome studies at the 650 band level and FISH. *Clinical diagnosis **Consensus diagnostic criteria were developed in 1993 **Major Criteria ***Neonatal and infantile hypotonia with poor suck ***Feeding problems and/or FTT in infancy ***Onset of rapid weight gain between 1-6 years of age causing central obesity ***Hyperphagia ***Characteristic facial features ***Hypogonadism ****Genital hypoplasia ****Incomplete and delayed puberty ****Infertility ***Developmental delay or mild to moderate MR or multiple learning disabilities **Minor Criteria ***Decreased fetal movement and infantile lethargy ***Typical behavior problems ***Sleep disturbance/sleep apnea ***Short stature for the family by 15 years of age ***Hypopigmentation ***Small hands and feed for height age ***Narrow hands with straight ulnar border ***Esotropia, myopia ***Thick, viscous saliva ***Speech articulation defects ***Skin picking **Supportive Findings ***High pain threshold ***Decreased vomiting ***Scoliosis and/or kyphosis ***Early adrenarche ***Osteoporosis ***Unusual skill with jigsaw puzzles ***Normal neuromuscular studies such as muscle biopsy Differential Diagnosis *Hypotonia in infancy **Neonatal sepsis **CNS depression **Congenital myotonic dystrophy **Several myopathies and neuropathies *Developmental delay/mental retardation, obesity, and hypogonadism **Albright hereditary osteodystrophy **Bardet-Biedl syndrome **Cohen syndrome **Borjeson-Forssman-Lehmann syndrome **Some patients with Fragile X syndrome **Possible 6q or 1p deletions Management *Infancy **Special feeding techniques, including special nipples or gavage feeding to assure adequate nutrition **Physical therapy may improve muscle strength and encourage achievement of milestones **Screening for strabismus should start in infancy *Childhood **Obesity ***Monitoring of weight and nutritional counseling are critical ***Low-calrie, well-balanced diet with regular exercise and close supervision to minimize food stealing should be instituted before the onset of excessive weight gain ***Energy requirement should rarely exceed 1000 to 1200 Kcal/day **Learning disabilities should be evaluated, and educational planning instigated **Speech therapy is often needed **Growth hormone replacement ***Normalizes height and increases lean body mass ***Growth hormone evaluation is recommended if growth rate is reduced or height is less than the 3rd percentile **Behavioral disturbances ***Often follow excessive weight gain ***Firm limit-setting should be instituted ***Serotonin re-uptake inhibitors have helped many patients with managing behavior **Sex hormone replacement is controversial ***Produces adequate secondary sexual characteristis ***Testosterone replacement may play a role in male behavior problems ***Estrogen replacement may increase risk of stroke and osteoporosis in females **Scoliosis screening should be routine *Adulthood **Obesity ***The major cause of morbidity and mortality in adults ***Can cause medical complications ****Cardiopulmonary compromise ****Type II diabetes mellitus ****Thrombophlebitis ****Chronic edema ***If obesity is avoided, longevity may be nearly normal **Psychiatric and behavioral disturbances may require hospitalization and medication ***Psychosis ***Manic-depressive illness ***Obsessive-compulsive disorder **Group homes specifically designated for patients with P-W have been successful Prenatal Testing Psychosocial Issues *Uncertainty because symptoms and severity vary widely **Uncertainly may make goal-setting and future planning problematic *Feelings of isolation, loneliness, and despair. *Frustration due to ignorance about the disease. *Coping with chronic pain and fatigue *Burden of dealing with a chronic, rare, progressive disease *Body image and self-esteem issues due to spleen or liver enlargement or growth retardation *Guilt about passing on the gene to one's children. *Family dynamic changes **Stress in the marriage **Sibling relationships **Family members may feel guilty or resentful *Depression and frustration about the requirement for lifelong management. *Shock, fear, and denial over the diagnosis. Offer Resources *Prader-Willi Syndrome Association **(800) 926-4797 **www.pwsausa.org *The Prader-Willi Foundation **(800) 253-7993 **PWSAUSA@aol.com *March of Dimes information on Spina Bifida, Amniocentesis, Folic Acid, and Maternal blood screening **www.modimes.org 1-888-MODIMES Review and summarize major points Elicit final questions and concerns Arrange for Follow-up References *National Organization for Rare Disorders *Online Mendelian Inheritance in Man *Geneclinics GeneReviews *Living with Gaucher Disease: A guide for patients, parents, relatives, and friends **Brochure copyright 1991, Genzyme Corporation *Charrow, J. et al. "Gaucher Disease: Recommendations on Diagnosis, Evaluation, and Monitoring." Archives of Internal Medicine; vol 158, p 1754, September 14, 1998. Notes The information in this outline was last updated in 2002. 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